Virtually all patients with Down Syndrome (DS) develop Alzheimer?s disease (AD)-like neuropathologies including Amyloid-? (A?) neuritic plaques, synaptic dysfunction and neurodegeneration. While the extra copy of A? Precursor Protein (APP) on chromosome 21 is thought to play a major role in the development of this type of pathology in DS, the underlying mechanisms responsible for these changes and their precise contribution to neurodegeneration and dementia have remained largely elusive. Compelling evidence supports the hypothesis that the subcellular localization and trafficking of APP via the vacuolar protein sorting complex is of critical importance for A? production in vivo. However, no data are available on the role that the system plays in the AD-like DS pathogenesis. In our preliminary studies, we found that the vacuolar protein sorting-associated 35 (Vps35), a major component of the retromer complex recognition core, directly modulates APP metabolism and governs its trafficking. Vps35 is abundantly expressed in the central nervous system, and its knock-out in mice results in neuropathologies resembling those found in AD and DS patients. In other preliminary studies we found that compared with controls, DS brains have a significant reduction in Vps35 levels, which is also evident in brains from a transgenic mouse model of DS, Ts65Dn mice. We hypothesize that Vps35 down-regulation in DS is responsible for the development of the AD-like phenotype in these subjects and represents a novel therapeutic target for neurodegeneration and dementia. In this proposal, we will assess the temporal relationship between dysregulation of Vps35 in the brains of DS patients and the development of the AD-like neuropathology. We will then investigate whether a pharmacological chaperone by increasing Vps35 levels in the central nervous system of a relevant DS transgenic mouse model will produce neuroprotective effects. Finally, we will determine whether increase brain Vps35 expression level will protect against the neuropathology and cognitive decline that occur in the same mouse model. The results of our proposed studies will elucidate the functional role that Vps35 plays in neurodegeneration providing novel molecular mechanisms for disease pathogenesis/pathology and most importantly new therapeutic opportunities for delaying and/or treating the AD-like phenotype of DS.